The aim of this work has been to investigate the mechanisms underlying the lateralized response to fronto-lateral cortical lesions in the rat. During the present grant period, we demonstrated that lateralized hyperactivity can be elicited by the noradrenergic neurotoxin DSP-4 but noradrenergic depletions are not necessary, since disc shaped lesions of the white matter underlying the cortex will also elicit the lateralized response. This finding led us to examine the role of subcortical structures. Electrolytic lesions of the nucleus accumbens produced hyperactivity following right but not left hemisphere lesions. During the present grant period, we also found that female rats do not show the lateralized response to cortical lesions found in males. In addition, behavorial asymmetry can not be produced prior to puberty (ie. no asymmetry was found in 25, 30 or 55 day old rats). Asymmetry was found in 90 day male rats but not if they were castrated prior to puberty. This asymmetry could be restored, however, if castrated male rats were given testosterone implants after castration. These findings are the basis for the proposed studies designed to investigate two major questions. First, what the role of testosterone is in the production of cerebral laterality and secondly which subcortical sites that play a role in activity are asymmetrical. The proposed experiments involve developmental and sexual differentiation aspects of lateralization. We will study the role of testosterone in the production of lateralization in males. In addition, we will determine if hormonal induction of neural asymmetries are responsible for the absence of lateralized response in females. Finally, we will examine the perinatal factors which determine the neural substrate leading to post pubertal lateralization. The second line of proposed research will examine whether specific subcortical brain structures which have been demonstrated to play a role in locomotion have a lateralized response to focal administration of agonist or antagonist drugs. These lines of research will then come together in the identification of which sexual and developmental factors lead to asymmetrical behavorial responses at specific anatomical loci.